Epigenetic modifications associated with prenatal environmental risk factors for neurodevelopmental psychiatric disorders

Abstract

Maternal Immune activation (MIA) has been highlighted to be a risk factor for neurodevelopmental disorders like schizophrenia and autism. Epidemiological studies have confirmed this association and studies on animal models from our group and others consistently support this relationship. The functions of genes implicated in the pathophysiology of neurodevelopmental disorders are known to be modulated by epigenetic changes such as DNA cytosine methylation. These epigenetic ‘marks’ can be modified by environmental exposures such as infection and diet. However, the possible link between MIA and epigenome has not been examined directly. In addition, whether the postulated epigenetic effects of MIA can be modified by omega-3 intervention warrants further investigation. In this study an MIA mouse model was used to investigate the postnatal epigenetic changes associated with exposure to the viral analogue PolyIC compared to saline control, on gestation day 9. Global genome methylation was estimated using LINE1 assay and a similar method was used to assay Mecp2 promoter methylation. An intervention to stabilise these changes was also attempted using diet supplemented with omega-3 polyunsaturated fatty acids. Epigenetic differences were characterised using next generation sequencing and PCR based assays in the DNA samples obtained from the offspring brain. Widespread epigenetic changes, including LINE1 and Mecp2 promoter hypomethylation were observed following exposure to inflammation during prenatal life (Chapter 3). These findings were partially replicated in a bigger sample size (Chapter 4). Omega-3 PUFA intervention did not alter Mecp2 and LINE1 methylation. In a more detailed study, 204 genes were identified as differentially methylated as a result of MIA exposure (Chapter 5). These included, 40 genes previously reported to be associated with schizophrenia and 4 genes associated with autism. The ‘top’ functional network was genes responsible for ‘nervous system development and function’. Omega-3 intervention modified the epigenetic profile, including a number of genes which were affected by MIA. Out of 204 differentially methylated genes, 165 were stabilised by omega-3 intervention. Thirty-one of these 165 had previously been implicated in schizophrenia. This series of experiments indicates that environmental and genetic risk factors may modulate similar biological pathways associated with neurodevelopmental disorders. This may enable early intervention and diagnosis of youth at risk. These experiments also provide some evidence for the potential to modify the epigenome, in this case using diet. This is important as further investigation may open new avenues for treatment.